Studies in B7-deficient mice reveal a critical role for B7 costimulation in both induction and effector phases of experimental autoimmune encephalomyelitis

The importance of B7 costimulation in regulating T cell expansion and perip heral tolerance suggests that it may also play a significant regulatory rol e in the development of autoimmune disease. It is unclear whether B7 costim ulation is involved only in the expansion of autoreactive T cells in the pe riphery, or if it is also required for effector activation of autoreactive T cells in the target organ for mediating tissue injury and propagating aut oimmune disease. In this study, the role of B7-CD28 costimulation and the r elative importance of B7 costimulators for the induction and effector phase s of experimental autoimmune encephalomyelitis (EAE) induced by myelin olig odendrocyte glycoprotein (MOG) peptide were examined. Wild-type, B7-1/B7-2- deficient mice, or CD28-deficient C57BL/6 mice were immunized with MOG 35-5 5 peptide. Mice lacking both B7-1 and B7-2 or CD28 showed no or minimal cli nical signs of EAE and markedly reduced inflammatory infiltrates in the bra in and spinal cord. However, mice lacking either B7-1 or B7-2 alone develop ed clinical and pathologic EAE that was comparable to EAE in wild-type mice , indicating overlapping functions for B7-1 and B7-2. Resistance to EAE was not due to a lack of induction of T helper type 1 (Th1) cytokines, since T cells from B7-1/B7-2(-/-) mice show reduced proliferative responses, but g reater interferon gamma production compared with T cells from wild-type mic e. To study the role of B7 molecules in the effector phase of the disease, MOG 35-55 specific T lines were adoptively transferred into the B7-1/B7-2(- /-) and wild-type mice. Clinical and histologic EAE were markedly reduced i n B7-1/B7-2(-/-) compared with wild-type recipient mice. These results demo nstrate that B7 costimulation has critical roles not only in the initial ac tivation and expansion of MOG-reactive T cells, but also in the effector ph ase of encephalitogenic T cell activation within the central nervous system .